Sialic acid analogs

ABSTRACT

The present invention provides sialic acid analogs and their compositions useful for the treatment of sialic acid deficiencies.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.16/050,343, filed on Jul. 31, 2018, which is a continuation of U.S.patent application Ser. No. 14/944,779, filed on Nov. 18, 2015, now U.S.Pat. No. 10,065,981, which is a continuation of U.S. patent applicationSer. No. 14/461,295, filed on Aug. 15, 2014, now U.S. Pat. No.9,221,858, which is a continuation of U.S. patent application Ser. No.13/659,550, filed on Oct. 24, 2012, now U.S. Pat. No. 8,840,926, whichclaims priority to U.S. Provisional Application No. 61/550,610, filed onOct. 24, 2011, the disclosures of each of which are herein incorporatedby reference in their entireties for all purposes.

FIELD OF THE INVENTION

The present invention relates to sialic acid analogs useful for treatinga sialic acid deficiency.

BACKGROUND OF THE INVENTION

Sialic acid generally refers to the N- or O-substituted derivatives ofneuraminic acid, a monosaccharide with a nine-carbon backbone. The mostcommon member of this group is N-acetylneuraminic acid (also known asNeu5Ac or NANA) and thereby the term “sialic acid” is often used as thename of N-acetylneuraminic acid. It is the only sugar that contains anet negative charge and is typically found on terminating branches ofN-glycans, O-glycans, and glycosphingolipids (gangliosides) (andoccasionally capping side chains of GPI anchors). The sialic acidmodification of cell surface molecules is crucial for many biologicalphenomena including protein structure and stability, regulation of celladhesion, and signal transduction. Thus, sialic acid abnormalities, suchas sialic acid deficiency, can cause severe health problems. Sialic aciddeficiency disorders, such as Hereditary Inclusion Body Myopathy (HIBMor HIBM type 2), Nonaka myopathy, Distal Myopathy with Rimmed Vacuoles(DMRV) and most recently renamed GNE myopathy are a clinical diseaseresulting from a reduction in sialic acid production.

The biosynthesis steps and feedback regulation of GNE/MNK is depicted inFIG. 1. The production of sialic acid on glycoconjugates requires theconversion of N-acetylglucosamine (conjugated to its carrier nucleotidesugar UDP) to sialic acid. The sialic acid subsequently enters thenucleus where it is conjugated with its nucleotide sugar carrier CMP tomake CMP-sialic acid, which is used as a donor sugar for glycosylationreactions in the cell. CMP-sialic acid is a known regulator of GNE/MNKactivity. Jay et al., Gene Reg. & Sys. Biol. 3:181-190 (2009). Patientswith HIBM have a deficiency in the production of sialic acid via therate controlling enzyme GNE/MNK, which conducts the first two steps ofthis sequence: 1) epimerization of the glucosamine moiety to mannosaminewith release of UDP, and 2) phosphorylation of the N-acetylmannosamine.The mutations causing HIBM occur in the regions encoding either theepimerase domain (GNE) or the kinase domain (MNK). Nearly twenty GNEmutations have been reported in HIBM patients from different ethnicbackgrounds with founder effects among the Iranian Jews and Japanese.Broccolini et al., Hum. Mutat. 23:632 (2004). Most are missensemutations and result in decreased enzyme GNE activity andunderproduction of sialic acid. Sparks et al., Glycobiology15(11):1102-10 (2005); Penner et al., Biochemistry 45:2968-2977 (2006).

Researchers have investigated the use of sialic acid in substratereplacement therapy for treating sialic acid deficiency disorders andachieved some promising results in the preliminary studies.

SUMMARY OF THE INVENTION

The present invention provides novel sialic acid analogs useful fortreating any sialic acid deficiency disorders and methods of treatingand preventing sialic acid deficiencies utilizing the present compoundsand the pharmaceutical compositions or formulations thereof.

In one embodiment, the present application provides a compound havingstructural Formula (I):

or a pharmaceutically acceptable salt or solvate thereof; wherein:

R², R³, R⁴, and R⁶ are independently hydrogen or a moiety selected fromstructural formula (a), (b), (c), (d), (e), (f), and (g):

R¹ is a moiety selected from structural formula (a), (b), (c), (f), and(g); or a nucleoside phosphate moiety;

X is oxygen or sulfur;

L¹ and L² are each independently a covalent bond, —O—, or —NR^(10a)—;

R^(10a) is hydrogen or optionally substituted alkyl;

R^(10a) and R^(2a) are each independently hydrogen, optionallysubstituted alkyl, optionally substituted heteroalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl,—X^(a)—C(O)—O—R^(11a), or —X^(a)—O—C(O)—O—R^(11a);

X^(a) is optionally substituted alkylene;

each R^(11a) is independently hydrogen, optionally substituted alkyl, oroptionally substituted heteroalkyl;

R^(3a) is optionally substituted alkyl; or alternatively, R^(3a),together with the carboxyl moiety to which it is attached, form amonopeptidyl or dipeptidyl group;

each R^(8a) and R^(9a) is independently hydrogen or optionallysubstituted alkyl;

m is 1 or 2;

Z is hydrogen, lower alkyl, an amide group, a lactam group, an estergroup, a lactone group, an urea group, a cyclic urea group, a carbonategroup, a cyclic carbonate group, a carbamate group, a cyclic carbamategroup, or a moiety selected from (a), (b), (c), and (f);

R⁵ is hydrogen, G⁺, optionally substituted alkyl, or a moiety selectedfrom (a), (b), (c), (f), and (g); and

G⁺ is a charged organic amine moiety; or alternatively,

OR³ and OR⁶ are taken together to form a lactone structure representedby Formula (Ia):

with the following provisos:

(a) at least one of R¹, R², R³, R⁴, R⁵, and R⁶ is not H; and

(b) R^(3a) is not optionally substituted alkyl unless (1) OR³ and OR⁶are taken together to form a lactone structure of Formula (Ia), or (2)R⁵ is (f).

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention, or apharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable carrier.

In yet another embodiment, the present invention provides a sustainedrelease pharmaceutical composition comprising a compound of the presentinvention, or a pharmaceutically acceptable salt or solvate thereof,wherein the release of the compound is over a period of about four hoursor more.

In yet another embodiment, the present invention provides a sustainedrelease pharmaceutical composition comprising a compound of the presentinvention, or a pharmaceutically acceptable salt or solvate thereof,wherein the pharmacological effect from the compound lasts about fourhours or more upon administration of the composition.

In yet another embodiment, the present invention provides a sustainedrelease pharmaceutical composition comprising a compound of the presentinvention, or a pharmaceutically acceptable salt or solvate thereof;wherein the composition, upon administration, provides a therapeuticallyeffective amount of the compound for about 4 hours or more.

In one embodiment, the present invention provides a method for treatinga sialic acid deficiency in a patient in need thereof comprisingadministering an effective amount of a compound of the presentinvention, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the present invention provides a method fortreating a sialic acid deficiency in a patient in need thereofcomprising administering a compound of the present invention, or apharmaceutically acceptable salt or solvate thereof; wherein uponadministration, the compound, or a pharmaceutically acceptable salt orsolvate thereof, continuously provides a therapeutically effectiveamount of sialic acid for about 4 hours to about 24 hours.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows the biosynthetic pathway of sialic acid in its subcellularlocations.

FIGS. 2A-2C are graphs demonstrating the data from a single dose POcrossover pharmacokinetics study of sialic acid and Compound 1 incynomolgus monkeys.

FIGS. 3A-3D show pharmacokinetic data obtained following single doseoral administration of various compounds of the present invention tomale Sprague Dawley rats.

FIG. 4A-4D show pharmacokinetic data obtained following single dose oraladministration of various compounds of the present invention to maleSprague Dawley rats.

DETAILED DESCRIPTIONS OF THE INVENTION

Various embodiments and advantages of the present invention will be setforth in part in the description that follows, and in part will beobvious from the description, or may be learned by practice of theinvention. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the invention as described.

Definitions

The terms “a” and “an” do not denote a limitation of quantity, butrather denote the presence of at least one of the referenced item. Theterm “or” or “and/or” is used as a function word to indicate that twowords or expressions are to be taken together or individually. The terms“comprising”, “having”, “including”, and “containing” are to beconstrued as open-ended terms (i.e., meaning “including, but not limitedto”). The endpoints of all ranges directed to the same component orproperty are inclusive and independently combinable.

Reference to “about” a value or parameter herein includes (anddescribes) variations that are directed to that value or parameter perse. For example, description referring to “about X” includes descriptionof “X”.

The term “present compound(s)” or “compound(s) of the present invention”refers to compounds encompassed by structural formulae disclosed hereinand includes any subgenus and specific compounds within these formulaewhose structure is disclosed herein. Compounds may be identified eitherby their chemical structure and/or chemical name. When the chemicalstructure and chemical name conflict, the chemical structure isdeterminative of the identity of the compound. The compounds describedherein may contain one or more chiral centers and/or double bonds andtherefore, may exist as stereoisomers, such as double-bond isomers(i.e., geometric isomers), enantiomers or diastereomers. Accordingly,the chemical structures depicted herein encompass all possibleenantiomers and stereoisomers of the illustrated compounds including thestereoisomerically pure form (e.g., geometrically pure, enantiomericallypure or diastereomerically pure) and enantiomeric and stereoisomericmixtures. Enantiomeric and stereoisomeric mixtures can be resolved intotheir component enantiomers or stereoisomers using separation techniquesor chiral synthesis techniques well known to the skilled artisan. Thecompounds may also exist in several tautomeric forms including the enolform, the keto form and mixtures thereof. Accordingly, the chemicalstructures depicted herein encompass all possible tautomeric forms ofthe illustrated compounds. The compounds described also includeisotopically labeled compounds where one or more atoms have an atomicmass different from the atomic mass conventionally found in nature.Examples of isotopes that may be incorporated into the compounds of theinvention include, but are not limited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O , etc. Compounds may exist in unsolvated forms as well as solvatedforms, including hydrated forms and as N-oxides. In general, compoundsmay be hydrated, solvated or N-oxides. Certain compounds may exist inmultiple crystalline or amorphous forms. In general, all physical formsare equivalent for the uses contemplated herein and are intended to bewithin the scope of the present invention. Further, it should beunderstood, when partial structures of the compounds are illustrated,that brackets indicate the point of attachment of the partial structureto the rest of the molecule. The term “tautomer” as used herein refersto isomers that change into one another with great ease so that they canexist together in equilibrium.

“Alkyl,” by itself or as part of another substituent, refers to asaturated branched, straight-chain or cyclic monovalent hydrocarbonradical derived by the removal of one hydrogen atom from a single carbonatom of a parent alkane. The term “alkyl” includes “cycloakyl” asdefined herein below. Typical alkyl groups include, but are not limitedto, methyl; ethyl; propyls such as propan-1-yl, propan-2-yl (isopropyl),cyclopropan-1-yl, etc.; butanyls such as butan-1-yl, butan-2-yl(sec-butyl), 2-methyl-propan-1-yl (isobutyl), 2-methyl-propan-2-yl(t-butyl), cyclobutan-1-yl, etc.; and the like. In some embodiments, analkyl group comprises from 1 to 20 carbon atoms (C₁-C₂₀ alkyl). In otherembodiments, an alkyl group comprises from 1 to 10 carbon atoms (C₁-C₁₀alkyl). In still other embodiments, an alkyl group comprises from 1 to 6carbon atoms (C₁-C₆ alkyl). C₁-C₆ alkyl is also known as “lower alkyl”.

It is noted that when an alkyl group is further connected to anotheratom, it becomes an “alkylene” group. In other words, the term“alkylene” refers to a divalent alkyl. For example, —CH₂CH₃ is an ethyl,while —CH₂CH₂— is an ethylene. That is, “Alkylene,” by itself or as partof another substituent, refers to a saturated or unsaturated, branched,straight-chain or cyclic divalent hydrocarbon radical derived by theremoval of two hydrogen atoms from a single carbon atom or two differentcarbon atoms of a parent alkane, alkene or alkyne. The term “alkylene”includes “cycloalkylene” as defined herein below. The term “alkylene” isspecifically intended to include groups having any degree or level ofsaturation, i.e., groups having exclusively single carbon-carbon bonds,groups having one or more double carbon-carbon bonds, groups having oneor more triple carbon-carbon bonds and groups having mixtures of single,double and triple carbon-carbon bonds. In some embodiments, an alkylenegroup comprises from 1 to 20 carbon atoms (C₁-C₂₀ alkylene). In otherembodiments, an alkylene group comprises from 1 to 10 carbon atoms(C₁-C₁₀ alkylene). In still other embodiments, an alkylene groupcomprises from 1 to 6 carbon atoms (C₁-C₆ alkylene).

“Alkenyl,” by itself or as part of another substituent, refers to anunsaturated branched, straight-chain or cyclic monovalent hydrocarbonradical having at least one carbon-carbon double bond derived by theremoval of one hydrogen atom from a single carbon atom of a parentalkene. The term “alkenyl” includes “cycloalkenyl” as defined hereinbelow. The group may be in either the cis or trans conformation aboutthe double bond(s). Typical alkenyl groups include, but are not limitedto, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl;cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl,2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl,buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl,cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.; and the like.

“Alkynyl,” by itself or as part of another substituent refers to anunsaturated branched, straight-chain or cyclic monovalent hydrocarbonradical having at least one carbon-carbon triple bond derived by theremoval of one hydrogen atom from a single carbon atom of a parentalkyne. Typical alkynyl groups include, but are not limited to, ethynyl;propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such asbut-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

“Alkoxy,” by itself or as part of another substituent, refers to aradical of the formula —O—R¹⁹⁹, where R¹⁹⁹ is alkyl or substituted alkylas defined herein.

“Acyl” by itself or as part of another substituent refers to a radical—C(O)R²⁰⁰, where R²⁰⁰ is hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl,substituted heteroalkyl, heteroarylalkyl or substituted heteroarylalkylas defined herein. Representative examples include, but are not limitedto formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl,benzoyl, benzylcarbonyl and the like.

“Aryl,” by itself or as part of another substituent, refers to amonovalent aromatic hydrocarbon group derived by the removal of onehydrogen atom from a single carbon atom of a parent aromatic ringsystem, as defined herein. Typical aryl groups include, but are notlimited to, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene and the like. In someembodiments, an aryl group comprises from 6 to 20 carbon atoms (C₆-C₂₀aryl). In other embodiments, an aryl group comprises from 6 to 15 carbonatoms (C₆-C₁₅ aryl). In still other embodiments, an aryl group comprisesfrom 6 to 15 carbon atoms (C₆-C₁₀ aryl).

“Arylalkyl,” by itself or as part of another substituent, refers to anacyclic alkyl group in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced withan aryl group as, as defined herein. That is, arylakyl can also beconsidered as an alkyl substituted by aryl. Typical arylalkyl groupsinclude, but are not limited to, benzyl, 2-phenylethan-1-yl,2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and thelike. Where specific alkyl moieties are intended, the nomenclaturearylalkanyl, arylalkenyl and/or arylalkynyl is used. In someembodiments, an arylalkyl group is (C₆-C₃₀) arylalkyl, e.g., thealkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C₁-C₁₀)alkyl and the aryl moiety is (C₆-C₂₀) aryl. In other embodiments, anarylalkyl group is (C₆-C₂₀) arylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the arylalkyl group is (C₁-C₅) alkyl and the arylmoiety is (C₆-C₁₂) aryl. In still other embodiments, an arylalkyl groupis (C₆-C₁₅) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety ofthe arylalkyl group is (C₁-C₅) alkyl and the aryl moiety is (C₆-C₁₀)aryl.

“Carbocyclic,” or “Carbocyclyl,” by itself or as part of anothersubstituent, refers to a saturated or partially saturated, buy notaromatic, cyclic monovalent hydrocarbon radical, including cycloalkyl,cycloalkenyl, and cycloalkynyl as defined herein. Typical carbocyclylgroups include, but are not limited to, groups derived fromcyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like. Insome embodiments, the cycloalkyl group comprises from 3 to 10 ring atoms(C₃-C₁₀ cycloalkyl). In other embodiments, the cycloalkyl groupcomprises from 3 to 7 ring atoms (C₃-C₇ cycloalkyl). The carbocyclyl maybe further substituted by one or more heteroatoms including, but notlimited to, N, P, O, S, and Si, which attach to the carbon atoms of thecycloalkyl via monovalent or multivalent bond.

“Heteroalkyl,” by themselves or as part of other substituents, refer toalkyl groups, in which one or more of the carbon atoms, are each,independently of one another, replaced with the same or differentheteroatoms or heteroatomic groups. Typical heteroatoms or heteroatomicgroups which can replace the carbon atoms include, but are not limitedto, —O—, —S—, —N—, —Si—, —NH—, —S(O)—, —S(O)₂—, —S(O)NH—, —S(O)₂NH— andthe like and combinations thereof. The heteroatoms or heteroatomicgroups may be placed at any interior position of the alkyl group.Typical heteroatomic groups which can be included in these groupsinclude, but are not limited to, —O—, —S—, —O—O—, —S—S—, —O—S—,—NR²⁰¹R²⁰²—, ═N—N═, —N═N—, —N═N—NR²⁰³R²⁰⁴, —PR²⁰⁵—, —P(O)₂—, —POR²⁰⁶—,—O—P(O)₂—, —SO—, —SO₂—, —SnR²⁰⁷R²⁰⁸— and the like, where R²⁰¹, R²⁰²,R²⁰³, R²⁰⁴, R²⁰⁵, R²⁰⁶, R²⁰⁷ and R²⁰⁸ are independently hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl or substitutedheteroarylalkyl.

“Heterocyclic,” or “Heterocyclyl,” by itself or as part of anothersubstituent, refers to a carbocyclic radical in which one or more carbonatoms are independently replaced with the same or different heteroatom.The heterocyclyl may be further substituted by one or more heteroatomsincluding, but not limited to, N, P, O, S, and Si, which attach to thecarbon atoms of the heterocyclyl via monovalent or multivalent bond.Typical heteroatoms to replace the carbon atom(s) include, but are notlimited to, N, P, O, S, Si, etc. Typical heterocyclyl groups include,but are not limited to, groups derived from epoxides, azirines,thiiranes, imidazolidine, morpholine, piperazine, piperidine,pyrazolidine, pyrrolidone, quinuclidine, and the like. In someembodiments, the heterocyclyl group comprises from 3 to 10 ring atoms(3-10 membered heterocyclyl) In other embodiments, the heterocyclylgroup comprise from 5 to 7 ring atoms (5-7 membered heterocyclyl). Acycloheteroalkyl group may be substituted at a heteroatom, for example,a nitrogen atom, with a (C₁-C₆) alkyl group. As specific examples,N-methyl-imidazolidinyl, N-methyl-morpholinyl, N-methyl-piperazinyl,N-methyl-piperidinyl, N-methyl-pyrazolidinyl and N-methyl-pyrrolidinylare included within the definition of “heterocyclyl.” A heterocyclylgroup may be attached to the remainder of the molecule via a ring carbonatom or a ring heteroatom.

“Halo,” by itself or as part of another substituent refers to a radical—F, —Cl, —Br or —I.

“Heteroaryl,” by itself or as part of another substituent, refers to amonovalent heteroaromatic radical derived by the removal of one hydrogenatom from a single atom of a parent heteroaromatic ring systems, asdefined herein. Typical heteroaryl groups include, but are not limitedto, groups derived from acridine, β-carboline, chromane, chromene,cinnoline, furan, imidazole, indazole, indole, indoline, indolizine,isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine,phenanthridine, phenanthroline, phenazine, phthalazine, pteridine,purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and thelike. In some embodiments, the heteroaryl group comprises from 5 to 20ring atoms (5-20 membered heteroaryl). In other embodiments, theheteroaryl group comprises from 5 to 10 ring atoms (5-10 memberedheteroaryl). Exemplary heteroaryl groups include those derived fromfuran, thiophene, pyrrole, benzothiophene, benzofuran, benzimidazole,indole, pyridine, pyrazole, quinoline, imidazole, oxazole, isoxazole andpyrazine.

“Heteroarylalkyl” by itself or as part of another substituent refers toan acyclic alkyl group in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced with aheteroaryl group. Where specific alkyl moieties are intended, thenomenclature heteroarylalkanyl, heteroarylakenyl and/orheteroarylalkynyl is used. In some embodiments, the heteroarylalkylgroup is a 6-21 membered heteroarylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the heteroarylalkyl is (C₁-C₆) alkyl and theheteroaryl moiety is a 5-15-membered heteroaryl. In other embodiments,the heteroarylalkyl is a 6-13 membered heteroarylalkyl, e.g., thealkanyl, alkenyl or alkynyl moiety is (C₁-C₃) alkyl and the heteroarylmoiety is a 5-10 membered heteroaryl.

An “amide” refers to an organic compound that contains the functionalgroup consisting of a carbonyl group linked to a nitrogen atom. Forexample, an amide group can be represented by the following structuralformula:

R is an optionally substituted hydrocarbon moiety;R′ and R″ are independently hydrogen or optionally substitutedhydrocarbon moiety.

A “lactam” group is a cyclic amide. That is, a lactam is an amide withthe above structural formula where R and R′ or R and R″, taken togetherwith the carbon and nitrogen atoms to which they are attached, form anoptionally substituted cyclic group.

An “ester” refers to an organic compound derived by reacting/condensingan oxoacid with a hydroxyl compound. For example, an amide group can berepresented by the following structural formula:

R and R′ are independently hydrogen or optionally substitutedhydrocarbon moiety.

A “lactone” group is a cyclic ester. That is, a lactone is an ester withthe above structural formula where R and R′, taken together with thecarbon and oxygen atoms to which they are attached, form an optionallysubstituted cyclic group which can be saturated, unsaturated, oraromatic.

A “urea” or “carbamide” refers to an organic compound having thefollowing structural formula:

R^(a), R^(b), R^(c), and R^(d) are independently hydrogen or optionallysubstituted hydrocarbon moiety.

A cyclic urea is a urea with the above structural formula where any twoof R^(a), R^(b), R^(c), and R^(d), taken together with the carbon andnitrogen atoms to which they are attached, form an optionallysubstituted cyclic group which can be saturated, unsaturated, oraromatic.

A “carbonate” refers to an organic compound having the followingstructural formula:

R′ and R″ are independently hydrogen or optionally substitutedhydrocarbon moiety.

A cyclic carbonate is a carbonate with the above structural formulawhere R′ and R″, taken together with the carbon and oxygen atoms towhich they are attached, form an optionally substituted cyclic groupwhich can be saturated, unsaturated, or aromatic.

A “carbamate” refers to an organic compound having the followingstructural formula:

R^(a), R^(b), and R^(c) are independently hydrogen or optionallysubstituted hydrocarbon moiety.

A cyclic carbamate is a carbamate with the above structural formulawhere any two of R^(a) and R^(b), or R^(a) and R^(c), taken togetherwith the carbon and nitrogen/oxygen atoms to which they are attached,form an optionally substituted cyclic group which can be saturated,unsaturated, or aromatic.

“Hydrocarbon” refers to an organic compound consisting of hydrogen andcarbon. Hydrocarbons can be straight, branched, or cyclic; and includearenes, alkanes, alkenes, cycloalkanes, alkynes, and etc. The term“substituted hydrocarbon” refers to a hydrocarbon where a carbon orhydrogen atom is replaced by an atom which is not carbon or hydrogen.The substituted hydrocarbons include substituted arenes, substitutedalkanes, heteroalkanes, substituted alkenes, heteroalkenes, substitutedcycloalkanes, heterocycloalkanes, substituted alkynes, and etc.

“Prodrug” refers to an inactive derivative of a therapeutically activeagent that will be converted to the active agent in vivo. That is, aprodrug is a precursor of a drug.

“Protecting group” refers to a grouping of atoms that when attached to areactive functional group in a molecule masks, reduces or preventsreactivity of the functional group. Examples of protecting groups can befound in Green et al., “Protective Groups in Organic Chemistry”, (Wiley,2^(nd) ed. 1991) and Harrison et al., “Compendium of Synthetic OrganicMethods”, Vols. 1-8 (John Wiley and Sons, 1971-1996). Representativeamino protecting groups include, but are not limited to, formyl, acetyl,trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl(“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl(“SES”), trityl and substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl(“NVOC”) and the like. Representative hydroxyl protecting groupsinclude, but are not limited to, those where the hydroxyl group iseither acylated or alkylated such as benzyl, and trityl ethers as wellas alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers andallyl ethers.

“Salt” refers to a salt of a compound, which possesses the desiredpharmacological activity of the parent compound. Such salts include: (1)acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound isreplaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike.

“Solvate” means a compound formed by solvation (the combination ofsolvent molecules with molecules or ions of the solute), or an aggregatethat consists of a solute ion or molecule, i.e., a compound of thepresent invention, with one or more solvent molecules. When water is thesolvent, the corresponding solvate is “hydrate”.

By “pharmaceutically acceptable” is meant a material that is notbiologically or otherwise undesirable, i.e., the material may beincorporated into a pharmaceutical composition administered to a patientwithout causing any significant undesirable biological effects orinteracting in a deleterious manner with any of the other components ofthe composition in which it is contained. When the term“pharmaceutically acceptable” is used to refer to a pharmaceuticalcarrier or excipient, it is implied that the carrier or excipient hasmet the required standards of toxicological and manufacturing testing orthat it is included on the Inactive Ingredient Guide prepared by theU.S. Food and Drug administration.

“N-oxide”, also known as amine oxide or amine-N-oxide, means a compoundthat derives from a compound of the present invention via oxidation ofan amine group of the compound of the present invention. An N-oxidetypically contains the functional group R₃N⁺—O⁻ (sometimes written asR₃N═O or R₃N→O).

“Substituted,” when used to modify a specified group or radical, meansthat one or more hydrogen atoms of the specified group or radical areeach, independently of one another, replaced with the same or differentsubstituent(s). Substituent groups useful for substituting saturatedcarbon atoms in the specified group or radical include, but are notlimited to —R^(a), halo, —O⁻, ═O, —OR^(b), —SR^(b), —S⁻, ═S,—NR^(c)R^(c), ═NR^(b), ═N—OR^(b), trihalomethyl, —CF₃, —CN, —OCN, —SCN,—NO, —NO₂, ═N₂, —N₃, —S(O)₂R^(b), —S(O)₂NR^(b), —S(O)₂O⁻, —S(O)₂OR^(b),—OS(O)₂R^(b), —OS(O)₂O⁻, —OS(O)₂OR^(b), —P(O)(O⁻)₂, —P(O)(OR^(b))(O⁻),—P(O)(OR^(b))(OR^(b)), —C(O)R^(b), —C(S)R^(b), —C(NR^(b))R^(b),—C(O)O⁻—, —C(O)OR^(b), —C(S)OR^(b), —C(O)NR^(c)R^(c),—C(NR^(b))NR^(c)R^(c), —OC(O)R^(b), —OC(S)R^(b), —OC(O)O⁻—,—OC(O)OR^(b), —OC(S)OR^(b), —NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b),—NR^(b)C(O)O—, —NR^(b)C(O)OR^(b), —NR^(b)C(S)OR^(b),—NR^(b)C(O)NR^(c)R^(c), —NR^(b)C(NR^(b))R^(b) and—NR^(b)C(NR^(b))NR^(c)R^(c), where R^(a) is selected from the groupconsisting of alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroaryl and heteroarylalkyl; each R^(b) is independentlyhydrogen or R^(a); and each R^(c) is independently R^(b) oralternatively, the two R^(c)s may be taken together with the nitrogenatom to which they are bonded form a 4-, 5-, 6- or 7-memberedcycloheteroalkyl which may optionally include from 1 to 4 of the same ordifferent additional heteroatoms selected from the group consisting ofO, N and S. As specific examples, —NR^(c)R^(c) is meant to include —NH₂,—NH-alkyl, N-pyrrolidinyl and N-morpholinyl. As another specificexample, a substituted alkyl is meant to include -alkylene-O-alkyl,-alkylene-heteroaryl, -alkylene-cycloheteroalkyl, -alkylene-C(O)OR^(b),-alkylene-C(O)NR^(b)R^(b), and —CH₂—CH₂—C(O)—CH₃. The one or moresubstituent groups, taken together with the atoms to which they arebonded, may form a cyclic ring including cycloalkyl andcycloheteroalkyl.

Similarly, substituent groups useful for substituting unsaturated carbonatoms in the specified group or radical include, but are not limited to,—R^(a), halo, —O⁻, —OR^(b), —SR^(b), —S⁻, —NR^(c)R^(c), trihalomethyl,—CF₃, —CN, —OCN, —SCN, —NO, —NO₂, —N₃, —S(O)₂R^(b), —S(O)₂O⁻,—S(O)₂OR^(b), —OS(O)₂R^(b), —OS(O)₂O⁻, —OS(O)₂OR^(b), —P(O)(O⁻)₂,—P(O)(OR^(b))(O⁻), —P(O)(OR^(b))(OR^(b)), —C(O)R^(b), —C(S)R^(b),—C(NR^(b))R^(b), —C(O)O⁻, —C(O)OR^(b), —C(S)OR^(b), —C(O)NR^(c)R^(c),—C(NR^(b))NR^(c)R^(c), —OC(O)R^(b), —OC(S)R^(b), —OC(O)O⁻, —OC(O)OR^(b),—OC(S)OR^(b), —NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b), —NR^(b)C(O)O⁻,—NR^(b)C(O)OR^(b), —NR^(b)C(S)OR^(b), —NR^(b)C(O)NR^(c)R^(c),—NR^(b)C(NR^(b))R^(b) and —NR^(b)C(NR^(b))NR^(c)R^(c), where R^(a),R^(b) and R^(c) are as previously defined.

Substituent groups useful for substituting nitrogen atoms in heteroalkyland cycloheteroalkyl groups include, but are not limited to, —R^(a),—O⁻, —OR^(b), —SR^(b), —S⁻, —NR^(c)R^(c), trihalomethyl, —CF₃, —CN, —NO,—NO₂, —S(O)₂R^(b), —S(O)₂O⁻, —S(O)₂OR^(b), —OS(O)₂R^(b), —OS(O)₂O⁻,—OS(O)₂OR^(b), —P(O)(O⁻)₂, —P(O)(OR^(b))(O′), —P(O)(OR^(b))(OR^(b)),—C(O)R^(b), —C(S)R^(b), —C(NR^(b))R^(b), —C(O)OR^(b), —C(S)OR^(b),—C(O)NR^(c)R^(c), —C(NR^(b))NR^(c)R^(c), —OC(O)R^(b), —OC(S)R^(b),—OC(O)OR^(b), —OC(S)OR^(b), —NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b),—NR^(b)C(O)OR^(b), —NR^(b)C(S)OR^(b), —NR^(b)C(O)NR^(c)R^(c),—NR^(b)C(NR^(b))R^(b) and —NR^(b)C(NR^(b))NR^(c)R^(c), where R^(a),R^(b) and R^(c) are as previously defined. Substituent groups from theabove lists useful for substituting other specified groups or atoms willbe apparent to those of skill in the art.

The term “substituted” specifically envisions and allows for one or moresubstitutions that are common in the art. However, it is generallyunderstood by those skilled in the art that the substituents should beselected so as to not adversely affect the useful characteristics of thecompound or adversely interfere with its function. Suitable substituentsmay include, for example, halogen groups, perfluoroalkyl groups,perfluoroalkoxy groups, alkyl groups, alkenyl groups, alkynyl groups,hydroxy groups, oxo groups, mercapto groups, alkylthio groups, alkoxygroups, aryl or heteroaryl groups, aryloxy or heteroaryloxy groups,arylalkyl or heteroarylalkyl groups, arylalkoxy or heteroarylalkoxygroups, amino groups, alkyl- and dialkylamino groups, carbamoyl groups,alkylcarbonyl groups, carboxyl groups, alkoxycarbonyl groups,alkylaminocarbonyl groups, dialkylamino carbonyl groups, arylcarbonylgroups, aryloxycarbonyl groups, alkylsulfonyl groups, arylsulfonylgroups, cycloalkyl groups, cyano groups, C₁-C₆ alkylthio groups,arylthio groups, nitro groups, keto groups, acyl groups, boronate orboronyl groups, phosphate or phosphonyl groups, sulfamyl groups,sulfonyl groups, sulfinyl groups, and combinations thereof. In the caseof substituted combinations, such as “substituted arylalkyl,” either thearyl or the alkyl group may be substituted, or both the aryl and thealkyl groups may be substituted with one or more substituents.Additionally, in some cases, suitable substituents may combine to formone or more rings as known to those of skill in the art.

The term “optionally substituted” denotes the presence or absence of thesubstituent group. For example, optionally substituted alkyl includesboth unsubstituted alkyl and substituted alkyl. The substituents used tosubstitute a specified group can be further substituted, typically withone or more of the same or different groups selected from the variousgroups specified above.

“Carrier” refers to a diluent, adjuvant, excipient or vehicle with whicha compound is administered.

The term “amino acid” refers to an organic compound containing an aminogroup (NH₂), a carboxylic acid group (COOH), and any of various sidegroups. For example, the twenty two amino acids that are naturallyincorporated into polypeptides (a.k.a. natural amino acids or naturallyoccurring amino acids) have the structural formula NH₂CHRCOOH, wherein Ris a moiety including hydrogen, optionally substituted hydrocarbonmoiety, etc. It is commonly known that certain amino acids have twostereoisomers designated as L and D amino acids. Amino acids asmentioned herein include L isomer, D isomer, or a mixture thereof.Furthermore, any of the L, D, or mixed amino acids may further containadditional stereoisomeric center(s) in their structures.

The term “peptidyl group”, as used herein, denotes an organic moietyderived from one or more amino acid(s) by removal of a hydrogen atomfrom the NH₂ and/or OH group of the amino acid(s). When the peptidylgroup is derived from a single amino acid, it is a monopeptidyl group.When the peptidyl group is derived from a molecule of multiple aminoacids, it is a multipeptidyl group, e.g., dipeptidyl or tripeptidyl. Theamino acids in a multipeptidyl group is linked with each other via amidebond(s).

By “immediate-release” or “instant-release”, it is meant a conventionalor non-modified release in which greater than or equal to about 75% ofthe active agent is released within two hours of administration,specifically within one hour of administration.

By “sustained release”, it is meant a dosage form in which the releaseof the active agent is controlled or modified over a period of time.Sustained can mean, for example, extended-, controlled-, delayed-,timed-, or pulsed-release at a particular time. Alternatively,controlled can mean that the release of the active agent is extended forlonger than it would be in an immediate-release dosage form, e.g., atleast over several hours.

By “effective amount” or “therapeutically effective amount” it is meantthe amount of the present compound that, when administered to a patientfor treating a disease, such as one related to sialic acid deficiency,is sufficient to effect such treatment for the disease. The “effectiveamount” or “therapeutically effective amount” will vary depending on theactive agent, the disease and its severity, and the age, weight, andother conditions of the patient to be treated.

The terms “treating” and “treatment”, as used herein, refer to anapproach for obtaining beneficial or desired results including clinicalresults. For purposes of this invention, beneficial or desired clinicalresults include, but are not limited to, one or more of the following:decreasing the severity and/or frequency one or more symptoms resultingfrom the disease, diminishing the extent of the disease, stabilizing thedisease (e.g., preventing or delaying the worsening of the disease),delay or slowing the progression of the disease, ameliorating thedisease state, increasing production of sialic acid, the sialylationprecursor CMP-sialic acid (e.g., increasing intracellular production ofsialic acid) and restoring the level of sialylation in muscle and otherproteins, decreasing the dose of one or more other medications requiredto treat the disease, and/or increasing the quality of life. “Treating”a patient with a compound or composition described herein includesmanagement of an individual to inhibit or cause regression of a diseaseor condition.

“Prophylaxis” or “prophylactic treatment” “or preventive treatment”refers to prevention of the occurrence of symptoms and/or theirunderlying cause, for example, prevention of a disease or condition in apatient susceptible to developing a disease or condition (e.g., at ahigher risk, as a result of genetic predisposition, environmentalfactors, predisposing diseases or disorders, or the like). Prophylaxisincludes HIBM myopathy in which chronic disease changes in the musclesare irreversible and for which animal model data suggests treatmentbenefit in prophylaxis.

The term “patient” refers to an animal, for example, a mammal andincludes, but is not limited to, human, bovine, horse, feline, canine,rodent, or primate. Preferably, the patient is a human.

Embodiments of the Compounds

In one aspect, the present invention is directed to sialic acid analogswhich are converted, at least in part, to sialic acid uponadministration to a patient.

In one embodiment, the present invention is directed to a compoundrepresented by a structural Formula (I):

or a pharmaceutically acceptable salt or solvate thereof;

wherein:

R², R³, R⁴, and R⁶ are independently hydrogen or a moiety selected fromstructural formula (a), (b), (c), (d), (e), (f), and (g):

R¹ is a moiety selected from structural formula (a), (b), (c), (d), (e),(f), and (g); or a nucleoside phosphate moiety;

X is oxygen or sulfur;

L¹ and L² are each independently a covalent bond, —O—, or —NR^(10a)—;

R^(10a) is hydrogen or optionally substituted alkyl;

R^(1a) and R^(2a) are each independently hydrogen, optionallysubstituted alkyl, optionally substituted heteroalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl,—X^(a)—C(O)—O—R^(11a), or —X^(a)—O—C(O)—O—R^(11a);

X^(a) is optionally substituted alkylene;

each R^(11a) is independently hydrogen, optionally substituted alkyl, oroptionally substituted heteroalkyl;

R^(3a) is optionally substituted alkyl; or alternatively, R^(3a),together with the carboxyl moiety to which it is attached, form amonopeptidyl or dipeptidyl group;

each R^(8a) and R^(9a) is independently hydrogen or optionallysubstituted alkyl;

m is 1 or 2;

Z is hydrogen, lower alkyl, an amide group, a lactam group, an estergroup, a lactone group, an urea group, a cyclic urea group, a carbonategroup, a cyclic carbonate group, a carbamate group, a cyclic carbamategroup, or a moiety selected from (a), (b), (c), (d), (e), and (f);

R⁵ is hydrogen, G⁺, optionally substituted alkyl, or a moiety selectedfrom (a), (b), (c), (d), (e), (f), and (g); and

G⁺ is a charged organic amine moiety; or alternatively,

OR³ and OR⁶ are taken together to form a lactone structure representedby Formula (Ia):

with the following provisos:

(a) at least one of R¹, R², R³, R⁴, R⁵, and R⁶ is not H; and

(b) R^(3a) is not optionally substituted alkyl unless OR³ and OR⁶ aretaken together to form a lactone structure of Formula (Ia) or R⁵ is (f).

In one embodiment of the present invention, the structural Formula (I)is represented by structural Formula (II), and structural Formula (II)is represented by structural Formula (IIa):

R¹, R², R³, R⁴, R⁵, and R⁶ are the same as previously defined.

In one embodiment of structural Formula (I) or (II), R⁵ is hydrogen, Y⁺,optionally substituted alkyl, or structural formula (g).

In one embodiment of structural Formula (I) or (II), at least one of R²,R³, and R⁴ is hydrogen. In one embodiment of structural Formula (I) or(II), at least two of R², R³, and R⁴ are hydrogen. In one embodiment ofstructural Formula (I) or (II), R², R³, and R⁴ are hydrogen.

In one embodiment of structural Formula (I) or (II), R⁶ is hydrogen.

In one embodiment of structural Formula (I) or (II), m is 1; R^(8a) ishydrogen; and R^(9a) is hydrogen or lower alkyl.

In one embodiment of structural Formula (I) or (II), R¹ is selected fromstructural formula (a), (b), (c), (d), (e), and (f); or a nucleosidephosphate moiety; and R², R³, R⁴, R⁵, and R⁶ are hydrogen.

In one embodiment of structural Formula (I) or (II), R¹ is selected fromstructural formula (a), (b), (c), (d), (e), and (f); or a nucleosidephosphate moiety; R², R³, R⁴, and R⁶ are hydrogen; and R⁵ is optionallysubstituted alkyl or structural formula (g).

In one embodiment of structural Formula (I) or (II), R¹ is structuralformula (a); and at least one of L¹ and L² is —O—. In one embodiment, R⁵is hydrogen or structural formula (g). In another embodiment, Z ishydrogen, lower alkyl, or structural formula (a). In yet anotherembodiment, wherein L¹ and L² are —O—. In yet another embodiment, R^(1a)and R^(2a) are independently hydrogen, optionally substituted loweralkyl, or optionally substituted aryl. In yet another embodiment, R²,R³, R⁴, and R⁶ are hydrogen.

In one embodiment of structural Formula (I) or (II), wherein R¹ isstructural formula (a); X is oxygen or sulfur; L¹ and L² are —O—; R^(1a)and R^(2a) are independently hydrogen, lower alkyl, or aryl; R², R³, R⁴,and R⁶ are hydrogen; R⁵ is hydrogen or structural formula (g); and Z ishydrogen, lower alkyl, or structural formula (a).

In one embodiment of structural Formula (I) or (II), R¹ is structuralformula (b) or (c); and L¹ is —O—. In one embodiment, R⁵ is hydrogen orstructural formula (g). In another embodiment, Z is hydrogen, loweralkyl, or structural formula (b) or (c). In yet another embodiment,R^(1a) is hydrogen, optionally substituted lower alkyl, or optionallysubstituted aryl. In yet another embodiment, R², R³, R⁴, and R⁶ arehydrogen.

In one embodiment of structural Formula (I) or (II), R¹ is structuralformula (b) or (c); L¹ is —O—; R^(1a) is hydrogen, lower alkyl, or aryl;R², R³, R⁴, and R⁶ are hydrogen; R⁵ is hydrogen or structural formula(g); and Z is hydrogen, lower alkyl, or structural formula (b) or (c).

In one embodiment of structural Formula (I) or (II), R¹ is structuralformula (f); R^(3a), together with the carboxyl moiety to which it isattached, form a monopeptidyl or dipeptidyl group; and the monopeptidylor dipeptidyl group is derived from naturally occurring amino acid,non-naturally occurring amino acid, or a combination thereof. In oneembodiment, the monopeptidyl or dipeptidyl group of R^(3a) is derivedfrom amino acids selected from the group consisting of Alanine,Arginine, Asparagine, Aspartic acid, Cysteine, Glutamic acid, Glutamine,Glycine, Histidine, Isoleucine, Leucine, Lysine, Methionine,Phenylalanine, Proline, Serine, Threonine, Tryptophan, Tyrosine, Valine,and a combination thereof.

In one embodiment of structural formula (f), the monopeptidyl group canbe represented by structural formula (d) and (e):

R^(4a) is hydrogen, halogen, nitro, cyano, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted aryl, optionallysubstituted heteroalkyl, optionally substituted heterocyclyl, optionallysubstituted heteroaryl, optionally substituted carbocyclyl, OR, NR₂, orSR; each R, R^(7a), R^(5a), and R^(6a) is independently hydrogen oroptionally substituted alkyl; or alternatively, R^(4a) andNR^(5a)R^(6a), together with the carbon atom to which they are attached,or R^(5a) and R^(6a), together with the nitrogen atom to which they areattached, form an optionally substituted four- to seven-memberedazacyclic ring which optionally contains one or more additionalheteroatom(s) selected from oxygen, nitrogen, and sulfur; and L³ isoptionally substituted alkylene.

In one embodiment of structural Formula (I) or (II), R¹ is structuralformula (d) or (e); R^(4a) is hydrogen, halogen, cyano, optionallysubstituted alkyl, optionally substituted heteroalkyl, OR, NR₂, or SR;R, R^(7a), R^(5a), and R^(6a) are independently hydrogen or lower alkyl;L³ is optionally substituted C1 to C6 alkylene; and the optionalsubstituent is selected from the group consisting of halogen, nitro,cyano, hydroxyl, alkoxy, amino, N-alkyl amino, N, N-dialkylamino, ═O,acyl, carboxyl, carboxyl ester, amide, optionally substituted aryl,optionally substituted heterocyclyl, optionally substituted heteroaryl,and optionally substituted carbocyclyl. In one embodiment, R⁵ ishydrogen or structural formula (g). In another embodiment, Z ishydrogen, lower alkyl, or structural formula (d) or (e). In yet anotherembodiment, R², R³, R⁴, and R⁶ are hydrogen.

In one embodiment of structural formula (f), the dipeptidyl group can berepresented by structural Formula (h) or (i):

wherein, R^(4a) and R^(5a) are the same as previously defined; R^(12a)is hydrogen, halogen, nitro, cyano, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted aryl, optionallysubstituted heteroalkyl, optionally substituted heterocyclyl, optionallysubstituted heteroaryl, optionally substituted carbocyclyl, ═O, OR, NR₂,or SR; R^(13a) and R^(14a) are independently hydrogen or optionallysubstituted alkyl; or alternatively, R^(12a) and NR^(13a)R^(14a),together with the carbon atom to which they are attached, or R^(13a) andR^(14a), together with the nitrogen atom to which they are attached,form an optionally substituted four- to seven-membered azacyclic ringwhich optionally contains one or more additional heteroatom(s) selectedfrom oxygen, nitrogen, and sulfur; R^(15a) and R^(16a) are independentlyhydrogen or optionally substituted alkyl; and L⁴ and L⁵ areindependently optionally substituted alkylene. In one embodiment, R⁵ ishydrogen or structural formula (g). In another embodiment, Z ishydrogen, lower alkyl, or structural formula (f). In yet anotherembodiment, R², R³, R⁴, and R⁶ are hydrogen.

In one embodiment of structural Formula (I) or (II), R¹, R², R³, R⁴, andR⁶ are hydrogen; and R⁵ is G⁺. In one embodiment, G is selected from thegroup consisting of choline, diolamine, diethylamine, t-butyl amine, andethanolamine.

In one embodiment of structural Formula (I) or (II), R¹, R², R³, R⁴, andR⁶ are hydrogen; and R⁵ is optionally substituted alkyl or structuralformula (g). In one embodiment, R⁵ is lower alkyl or structural formula(g); m is 1; R^(8a) is hydrogen; R^(9a) is hydrogen or lower alkyl; andZ is an amide group, a lactam group, an ester group, a lactone group, anurea group, a cyclic urea group, a carbonate group, a cyclic carbonategroup, a carbamate group, or a cyclic carbamate group.

In one embodiment of structural Formula (I) or (II), R¹ is a nucleosidephosphate moiety; and R², R³, R⁴, R⁵, and R⁶ are hydrogen. In oneembodiment, the nucleoside phosphate moiety is an adenosinemonophosphate (AMP) moiety or an adenosine triphosphate (ATP) moiety.

In one embodiment, the present invention provides a compound of Formula(III):

or a pharmaceutically acceptable salt or solvate thereof; wherein:

R^(1b), R^(2b), R^(3b), R^(4b), and R^(5b) are independently OH,—O—C(O)—Y, or —O—(CHR)_(n)—O—C(O)—Y; with the proviso that at least oneof R^(1b), R^(2b), R^(3b), and R^(4b) and R^(5b) is not OH;

n is 1 or 2;

R^(b) is hydrogen or lower alkyl;

each —O—C(O)—Y is independently a peptidyl moiety; and

the presence of one or more —O—C(O)—Y in Formula (III) increases theuptake of the compound thereof by peptide transporter 1 (PepT1) ascompared to the uptake of a compound of Formula (III) wherein R^(1b),R^(2b), R^(3b), R^(4b), and R^(5b) are OH.

In one embodiment, structural Formula (III) is represented by structuralFormula (IV):

R^(1b), R^(2b), R^(3b), R^(4b), and R^(5b) are the same as previouslydefined.

In one embodiment of structural Formula (III) or (IV), R^(2b), R^(3b),and R^(4b) are OH.

In one embodiment of structural Formula (III) or (IV), R^(1b) is—O—C(O)—Y and R^(5b) is OH.

In one embodiment of structural Formula (III) or (IV), R^(1b) is—O—C(O)—Y; and R^(5b) is —O—(CHR)_(n)—O—C(O)—Y.

In one embodiment of structural Formula (III) or (IV), the peptidylmoiety of is a monopeptidyl moiety derived from an amino acid selectedfrom the group consisting of Alanine, Arginine, Asparagine, Asparticacid, Cysteine, Glutamic acid, Glutamine, Glycine, Histidine,Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Proline, Serine,Threonine, Tryptophan, Tyrosine, and Valine. In another embodiment, themonopeptidyl moiety is derived from an amino acid selected from thegroup consisting of Aspartic acid, Lysine, Proline, and Valine.

In one embodiment of structural Formula (III) or (IV), the peptidylmoiety is a dipeptidyl moiety derived from any of two amino acidsselected from the group consisting of Alanine, Arginine, Asparagine,Aspartic acid, Cysteine, Glutamic acid, Glutamine, Glycine, Histidine,Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Proline, Serine,Threonine, Tryptophan, Tyrosine, Valine, and a combination thereof. Inanother embodiment, the dipeptidyl moiety is derived from (1) Asparticacid and Alanine, or (2) glutamic acid and Alanine.

In one embodiment of structural Formula (III) or (IV), n is 1; and R^(b)is hydrogen.

In one embodiment of structural Formula (I), the compound is representedby structural Formula (Ia):

wherein R¹, R², and R⁴ are hydrogen; and R⁶ is structural formula (d),(e), or (f).

In one embodiment of structural Formula (Ia), R⁶ is structural formula(f); and R^(3a) is C1 to C12 alkyl.

In one embodiment of structural Formula (Ia), wherein R⁶ is structuralformula (f); and R^(3a), together with the carboxyl moiety to which itis attached, form a monopeptidyl or dipeptidyl group.

In one embodiment of structural Formula (Ia), the monopeptidyl ordipeptidyl group is derived from naturally occurring amino acid,non-naturally occurring amino acid, or a combination thereof.

In one embodiment of the present invention, structural Formula (I) isrepresented by structural Formula (V):

wherein R^(1a) is structural (f), and R^(3a), together with the carboxylmoiety to which it is attached, form a monopeptidyl or dipeptidyl group;and R^(5a) is structural (f), and R^(3a) is optionally substitutedalkyl.

In one embodiment of structural Formula (V), R^(3a), together with thecarboxyl moiety to which it is attached, form a monopeptidyl group whichis derived from amino acids selected from the group consisting ofAlanine, Arginine, Asparagine, Aspartic acid, Cysteine, Glutamic acid,Glutamine, Glycine, Histidine, Isoleucine, Leucine, Lysine, Methionine,Phenylalanine, Proline, Serine, Threonine, Tryptophan, Tyrosine, andValine. In one embodiment, the monopeptidyl group is derived from aminoacids selected from the group consisting of Aspartic acid, Lysine,Proline, and Valine.

In one embodiment of structural Formula (V), R^(3a), together with thecarboxyl moiety to which it is attached, form a dipeptidyl group whichis derived from any two amino acids selected from the group consistingof Alanine, Arginine, Asparagine, Aspartic acid, Cysteine, Glutamicacid, Glutamine, Glycine, Histidine, Isoleucine, Leucine, Lysine,Methionine, Phenylalanine, Proline, Serine, Threonine, Tryptophan,Tyrosine, Valine, and a combination thereof. In one embodiment, thedipeptidyl group is derived from two amino acids selected from (1)Aspartic acid and Alanine, or (2) glutamic acid and Alanine.

In one embodiment of structural Formula (V), R^(1a) is structural (f),and R^(3a) is unsubstituted C1 to C6 alkyl.

In one embodiment of structural Formula (V), R^(1a) is structural (f),and R^(3a) is C1 to C6 alkyl substituted with one or more groupsselected from alkoxy, hydroxyl, amino, N-alkyl amino, N-dialkyl amino,halo, nitro, cyano, —C(O)—R′, —C(O)—NH2, —C(O)—NHR′, —C(O)—NR′R′,—C(O)—OH, —C(O)—OR′; or two substituents, together with the atoms towhich they are attached, form an optionally substituted carbocyclyl orheterocyclyl containing one or more heteroatom(s) selected fromnitrogen, oxygen, and sulfur; wherein each R′ is independently anoptionally substituted alkyl.

In some specific embodiments, the compounds of the present invention areselected from the group consisting of

Embodiments of the Utilities of the Present Compounds

In one embodiment of the present invention, the present compounds can beused for the treatment of sialic acid deficiencies by administering aneffective amount of the present compound, or a pharmaceuticallyacceptable salt or solvate thereof, to a patient in need of suchtreatment. In another embodiment, the method comprises administering apresent compound, or a pharmaceutically acceptable salt or solvatethereof, to a patient in need of such treatment; wherein uponadministration, the compound, or a pharmaceutically acceptable salt orsolvate thereof, continuously provides a therapeutically effectiveamount of sialic acid for more than about 4 hours.

In one embodiment, the sialic acid deficiency is a myopathy associatedwith sialic acid deficiency. In one embodiment, the myopathy associatedwith sialic acid deficiency is Hereditary Inclusion Body Myopathy(HIBM), Nonaka myopathy, and/or Distal Myopathy with Rimmed Vacuoles(DMRV).

In other embodiments, the method can continuously provide atherapeutically effective amount of sialic acid for a period from about1 hour to about 2, about 3, about 4, about 5, about 6, about 7, about 8,about 9, about 10, about 11, about 12, about 13, about 14, about 15,about 16, about 17, about 18, about 19, about 20, about 21, about 22,about 23, or about 24 hours.

In one embodiment, the therapeutically effective amount refers to theamount administered to the patient. In another embodiment, thetherapeutically effective amount refers to the amount delivered to thebloodstream of the individual. In yet another embodiment, thetherapeutically effective amount refers to the amount delivered tomuscle tissue of the individual. The present compounds, uponadministration, are converted to sialic acid in vivo. That is, thepresent compounds, upon administration, are metabolized to one or morecompounds in the sialic acid pathway or derivatives thereof (includingsialic acid itself).

In one embodiment, the present method can deliver to the blood stream ofa patient one or more compounds in the sialic acid pathway orderivatives thereof (including sialic acid itself) with a C_(max) ofabout 0.2 to about 40 μg/mL or about 2 to about 40 μg/mL. In anotherembodiment, the therapeutically effective amount denotes one or morecompounds in the sialic acid pathway or derivatives thereof (includingsialic acid itself) with a C_(max) of about 5 to about 40 μg/mL.

In one embodiment, the present method can deliver to the blood stream ofa patient one or more compounds in the sialic acid pathway orderivatives thereof (including sialic acid itself) with a trough levelof about 0.1 to about 20 μg/mL. In other embodiments, the present methodcan deliver to a patient in need of the treatment one or more compoundsin the sialic acid pathway or derivatives thereof (including sialic aciditself) with a trough level of about any one of 0.1-15 μg/mL, 0.1-10μg/mL, 0.1-5 μg/mL, 0.5-20 μg/mL, 0.5-15 μg/mL, 0.5-10 g/mL, 0.5-5μg/mL, 1-20 μg/mL, 1-15 μg/mL, 1-10 μg/mL, or 1-5 μg/mL or about any oneof 0.1, 0.5, 1 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 10, 11,12, 13, 14 or 15 μg/mL.

In one embodiment, a patient is administered about any of 0.1 to 40g/day, 0.2 to 20 g/day, 0.5 to 10 g/day, 0.5 to 5 g/day, or 0.5 to 4g/day of one or more of the present compound.

In one embodiment, a patient is administered about any of 0.2 g/day to 5g/day, 0.3 g/day to 4 g/day, or 0.5 g/day to 3 g/day of one or more ofthe present compounds.

In other embodiments, a patient is administered about any of 0.01-500mg/kg, 0.05-300 mg/kg, 0.1-150 mg/kg, 0.5-100 mg/kg, or 1-50 mg/kg ofone or more compounds of the present invention. In some embodiments, thepresent method is capable of delivering to a patient in need thereoffrom about any of 1 mg/kg and 40 mg/kg, 1.5 mg/kg and 35 mg/kg, or 2mg/kg and 30 mg/kg of one or more compounds in the sialic acid pathwayor derivatives thereof (including sialic acid itself).

Embodiments of Compositions and Routes of Administration

A compound of the present invention can be formulated as apharmaceutical composition. In one embodiment, such a compositioncomprises a present compound, or a pharmaceutically acceptable salt orsolvate thereof, and a pharmaceutically acceptable carrier. Thepharmaceutical composition can then be administered orally,parenterally, by inhalation spray, rectally, or topically in dosage unitformulations containing conventional nontoxic pharmaceuticallyacceptable carriers, adjuvants, and vehicles as desired. The amount ofactive ingredient that can be combined with the carrier materials toproduce a single dosage form varies depending upon the mammalian hosttreated and the particular mode of administration. Topicaladministration can also involve the use of transdermal administrationsuch, as transdermal patches or iontophoresis devices. The termparenteral as used herein includes subcutaneous injections, intravenous,intramuscular, intrasternal injection, or infusion techniques.Formulation of drugs is discussed in, for example, Hoover, John E.,REMINGTON'S PHARMACEUTICAL SCIENCES, Mack Publishing Co., Easton, Pa.;1975. Other examples of drug formulations can be found in Liberman, H.A. and Lachman, L., Eds., PHARMACEUTICAL DOSAGE FORMS, Marcel Decker,New York, N.Y., 1980.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that can be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables. Dimethyl acetamide, surfactantsincluding ionic and non-ionic detergents, polyethylene glycols can beused. Mixtures of solvents and wetting agents such as those discussedabove are also useful.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter, synthetic mono- di- or triglycerides, fatty acids andpolyethylene glycols that are sold at ordinary temperatures but liquidat the rectal temperature and will therefore melt in the rectum andrelease the drug.

Solid dosage forms for oral administration can include capsules,tablets, pills, powders, and granules. In such solid dosage forms, thecompounds of this invention are ordinarily combined with one or moreadjuvants appropriate to the indicated route of administration. Ifadministered per os, a compound of the invention can be admixed withlactose, sucrose, starch powder, cellulose esters of alkanoic acids,cellulose alkyl esters, talc, stearic acid, magnesium stearate,magnesium oxide, sodium and calcium salts of phosphoric and sulfuricacids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone,and/or polyvinyl alcohol, and then tableted or encapsulated forconvenient administration. Such capsules or tablets can contain acontrolled-release formulation as can be provided in a dispersion ofactive compound in hydroxypropylmethyl cellulose. In the case ofcapsules, tablets, and pills, the dosage forms can also comprisebuffering agents such as sodium citrate, magnesium or calcium carbonateor bicarbonate. Tablets and pills can additionally be prepared withenteric coatings.

For therapeutic purposes, formulations for parenteral administration canbe in the form of aqueous or non-aqueous isotonic sterile injectionsolutions or suspensions. These solutions and suspensions can beprepared from sterile powders or granules having one or more of thecarriers or diluents mentioned for use in the formulations for oraladministration. A compound of the invention can be dissolved in water,polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseedoil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/orvarious buffers. Other adjuvants and modes of administration are welland widely known in the pharmaceutical art.

Liquid dosage forms for oral administration can include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions can also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

The dosage regimen utilizing the compounds of the present invention incombination with an anticancer agent is selected in accordance with avariety of factors including type, species, age, weight, sex and medicalcondition of the patient; the severity of the condition to be treated;the route of administration; the renal and hepatic function of thepatient; and the particular compound or salt or ester thereof employed.A consideration of these factors is well within the purview of theordinarily skilled clinician for the purpose of determining thetherapeutically effective dosage amounts to be given to a person in needof the instant combination therapy.

Systemic administration may also include relatively noninvasive methodssuch as the use of suppositories, transdermal patches, transmucosaldelivery and intranasal administration. Oral administration is alsosuitable for compounds of the invention. Suitable forms include syrups,capsules, tablets, as is understood in the art.

Dosage levels are dependent on the nature of the condition, drugefficacy, the condition of the patient, the judgment of thepractitioner, and the frequency and mode of administration; optimizationof such parameters is within the ordinary level of skill in the art.

In one embodiment, the present invention provides a sustained releasepharmaceutical composition comprising a compound of the presentinvention, or a pharmaceutically acceptable salt or solvate thereof,wherein the release of the compound is over a period of about 4 hours ormore. In other embodiments, the release of the compound is over a periodof about 5, about 6, about 7, about 8, about 9, about 10, about 11,about 12, about 13, about 14, about 15, about 16, about 17, about 18,about 19, about 20, about 21, about 22, about 23, or about 24 hours.

In another embodiment, the present invention provides a sustainedrelease pharmaceutical composition comprising a compound of the presentinvention, or a pharmaceutically acceptable salt or solvate thereof,wherein the pharmacological effect from the compound lasts about 4 hoursor more upon administration of the composition. In other embodiments,the pharmacological effect from the compound lasts about 5, about 6,about 7, about 8, about 9, about 10, about 11, about 12, about 13, about14, about 15, about 16, about 17, about 18, about 19, about 20, about21, about 22, about 23, or about 24 hours.

In another embodiment, the present invention provides a sustainedrelease pharmaceutical composition comprising a compound of the presentinvention, or a pharmaceutically acceptable salt or solvate thereof;wherein the composition, upon administration, provides a therapeuticallyeffective amount of the compound for about 4 hours or more. In otherembodiments, the composition provides a therapeutically effective amountof the compound for about 5, about 6, about 7, about 8, about 9, about10, about 11, about 12, about 13, about 14, about 15, about 16, about17, about 18, about 19, about 20, about 21, about 22, about 23, or about24 hours.

In one embodiment of any of the above-described sustained releasepharmaceutical composition, the composition contains a matrix whichcomprises a compound of the present invention, or a pharmaceuticallyacceptable salt or solvate thereof; and one or more release ratecontrolling polymers. In one embodiment, the matrix is in form of a coreor a layer over a core.

In one embodiment, the matrix comprises one or more polymers selectedfrom the group consisting of a) at least one water-swellable, pHindependent polymer, b) at least one anionic, pH-dependent, gel-formingcopolymer, c) at least one cationic polymer, and d) at least onehydrocolloid polymer.

In one embodiment of any of the above-described sustained releasepharmaceutical composition, the composition contains a release ratecontrolling membrane disposed over: a pull layer comprising a compoundof the present invention, or a pharmaceutically acceptable salt orsolvate thereof, and an osmotic push layer; wherein the release ratecontrolling membrane has an orifice immediately adjacent to the pulllayer. In one embodiment, the pull layer further comprises a releaserate controlling polymer.

In one embodiment of any of the above-described sustained releasepharmaceutical composition, the composition comprise one or moreparticles, and each of the particles comprises an active core comprisinga compound of the present invention, or a pharmaceutically acceptablesalt or solvate thereof; and a release rate controlling polymer disposedover the core.

In one embodiment of any of the above-described sustained releasepharmaceutical composition, the composition comprises one or moreparticles, and each of the particles comprises an inert core, an activelayer comprising a compound of the present invention, or apharmaceutically acceptable salt or solvate thereof disposed over theinert core, and a release rate controlling polymer disposed over theactive layer.

Various sustained release systems for drugs have also been devised, andcan be applied to compounds of the invention. See, for example, U.S.Pat. No. 5,624,677, International Patent Application No.PCT/US2011/043910, and U.S. patent application Ser. No. 12/595,027; thedisclosures of which are incorporated herein by reference in theirentireties for all purposes.

PREPARATION AND EXAMPLES

Standard procedures and chemical transformation and related methods arewell known to one skilled in the art, and such methods and procedureshave been described, for example, in standard references such asFiesers' Reagents for Organic Synthesis, John Wiley and Sons, New York,N.Y., 2002; Organic Reactions, vols. 1-83, John Wiley and Sons, NewYork, N.Y., 2006; March J. and Smith M., Advanced Organic Chemistry, 6thed., John Wiley and Sons, New York, N.Y.; and Larock R. C.,Comprehensive Organic Transformations, Wiley-VCH Publishers, New York,1999. All texts and references cited herein are incorporated byreference in their entirety.

Reactions using compounds having functional groups may be performed oncompounds with functional groups that may be protected. A “protected”compound or derivatives means derivatives of a compound where one ormore reactive site or sites or functional groups are blocked withprotecting groups. Protected derivatives are useful in the preparationof the compounds of the present invention or in themselves; theprotected derivatives may be the biologically active agent. An exampleof a comprehensive text listing suitable protecting groups may be foundin T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition,John Wiley & Sons, Inc. 1999.

Synthesis of the examples of presented compounds is illustrated in thefollowing schemes and procedures. The general synthetic schemes andrelated procedures used for the preparation of the examples compoundsare given hereinafter.

Example 1. Preparation of N-Acetyl-B-neuraminic Acid Benzyl ester-(1-2)

Chemicals/Reagents & S. No. Solvents MW mmol Eq. Amt 1 Sialic Acid (1-1)309.37 64.7 1.0 20.0 g 2 HPLC grade water 100 mL 3 10% aqueous Cs₂CO₃Added until neutral pH. 4 Benzyl Bromide (d = 1.44 171.04 350 5.4 42 mLg/ml) 5 Dimethylformamide (DMF) 160 mL

In a 500 mL lyophilization vessel, Sialic acid (20.0 g, 64.7 mmol) isdissolved in HPLC grade water (100 mL). At room temperature, theresulting acidic solution is then neutralized to approximately pH 7.0(litmus paper) by the addition of a 10% aqueous solution of CesiumCarbonate. The resulting clear solution is frozen and placed on aLyophilizer for 1-2 days until a flaky dry white powder is obtained. Thepowder is then dissolved in anhydrous DMF (160 mL) and placed under anatmosphere of argon gas to give a light suspension (mostly soluble). Tothis is then added Benzyl Bromide (dropwise via syringe) at roomtemperature under an argon balloon, at which time the solution becomesclear. The solution is stirred overnight at room temperature leading tothe formation of a white suspension of cesium bromide. The white solid(not desired product) is filtered through a Celite pad and the padwashed with copious amounts of DMF. The DMF is then removed under highvacuum with the temperature bath not exceeding 50° C. to give a viscous,pale yellow syrup. In order to remove excess benzyl bromide, the syrupyresidue is triturated using a mixture of diethyl ether and hexanes(approx 2:1) and the solvent is decanted off. The remaining syrup isthen dissolved is a minimum of isopropanol and placed in the freezer forseveral hours. A precipitate forms at this time which is filteredthrough a Buchner funnel and collected to provide 10.95 g of pureN-Acetyl-β-neuraminic Acid Benzyl ester as a white solid. Diethyl etheris added in small amounts to the mother liquor to induce crystallizationof a second lot of product benzyl ester (625 mg). Total Yield=10.95(Crop 1)+625 mg. (crop 2)=11.58 g (52% yield). LC/MS: (+) ESI: m/z=400.1[M+1]; 422.1 [M+Na, major signal); retention time=2.53 min. ¹H NMR (400MHz, d⁴-MeOD) δ 7.31-7.46 (m, 5H), 5.25 (dd, J=22.0, 12.8 Hz), 3.92-4.11(m, 2H), 3.77-3.89 (m, 2H), 3.70-3.76 (m, 2H), 3.65 (dd, J=16.0, 8.0 Hz,1H), 3.52 (dd, J=9.2, 1.2 Hz, 1H), 2.26 (dd, J=13.2, 5.2 Hz, 1H), 2.03(s, 3H), 1.93 (dd, J=12.4, 11.2 Hz, 1H).

Example 2. Preparation of5-Acetylamino-6-[3-(2-benzyloxycarbonylamino-3-methyl-butyryloxy)-1,2-dihydroxy-propyl]-2,4-dihydroxy-tetrahydro-pyran-2-carboxylicacid benzyl ester (1-5)

Chemicals/Reagents & S. No. Solvents MW mmol Eq. Amt 1N-Acetyl-β-neuraminic Acid 399.39 4.88 1.0 1.95 g Benzyl ester (1-2) 2Carbobenzyloxy-L-Valine 251.28 5.37 1.1 1.35 g 3 1-Chloro-N,N,2-trimethyl- 133.6 6.34 1.3 847 mg. 1-propenylamine (Ghosez'(848 μL) Reagent) (d = 1.01) 4 Dichloromethane(anhydrous) 12.0 mL 5Pyridine(anhydrous) 8.0 mL

To a solution of Carbobenzyloxy-L-Valine (1.35 g, 5.37 mmol) inanhydrous dichloromethane (12 mL) at 0° C. under argon is added1-Chloro-N,N,-2-trimethyl-1-propenylamine (848 μL, 6.34 mmol) bydropwise addition via a syringe. The resulting solution is then stirredat 0° C. for 10 minutes resulting in a clear colorless solution. To thissolution is then added the N-Acetyl-β-neuraminic Acid Benzyl ester(1-2), previously dissolved in anhydrous pyridine (8.0 mL) via dropwiseaddition. The solution immediately turns yellow and is kept at 0° C. andunder an argon atmosphere for 3 hours. The cooling bath is then removedand the solution kept at rt for overnight resulting in a cloudysuspension. The solvents are removed under high vacuum being carefulthat the temperature bath does not exceed 50° C. to give a light yellowoil. In order to remove traces of pyridine, the oil is triturated withtoluene and again evaporated under high vacuum. The remaining oil isdissolved in minimum amount of dichloromethane (DCM) and loaded directlyunto a silica gel column (Silicycle-FLH-R10030B-ISO80, 80 g Cartridge)and purified by flash chromatography (Mobile Phase: DCM/Methanol=96/4 to88/12 over 24 minutes). Combination of the purest fractions yields 996mg (32% yield) of pure (1-5) as a white solid. LC/MS: (+) ESI: m/z=633.2[M+1]; 655.2 [M+Na, major signal); retention time=3.69 min. ¹H NMR (400MHz, d⁴-MeOD) δ 7.12-7.37 (m, 11H), 5.08-5.17 (m, 2H), 4.95-5.03 (m,2H), 4.28 (dd, J=11.6, 2.0 Hz, 1H, C-9), 4.18 (dd, J=11.6, 6.0 Hz, 1H,(C-9′), 4.05-4.06 (m, 1H), 3.91-3.98 (m, 1H), 3.89 (dd, J=10.5, 1.2 Hz,1H), 3.80-3.86 (m, 11H), 3.70 (t, 1H), 3.41-3.43 (m, 1H), 2.14 (dd,J=12.8, 4.8 Hz, 1H), 1.98-2.08 (m, 1H), 1.91 (s, 3H), 1.79-1.89 (m, 1H),0.80-0.84 (m, 6H); ¹³C NMR (400 mHz, d⁴-MeOD) δ 173.7, 170.9, 158.9,136.2, 137.1, 129.6, 129.5, 129.4, 129.1, 129.0, 128.8, 96.7, 72.0,70.3, 69.3, 68.3, 68.0, 67.8, 61.1, 54.4, 40.7, 32.1, 22.7, 19.6, 18.4.

Example 3. Preparation of5-Acetylamino-6-[3-(2-amino-3-methyl-butyryloxy)-1,2-dihydroxy-propyl]-2,4-dihydroxy-tetrahydro-pyran-2-carboxylicacid (1)

S. No. Chemicals/Reagents & Solvents MW mmol Eq. Amt 1 Benzyl Ester(1-5) 632.6 3.96 1.0 2.50 g 2 10% Palladium on Carbon 2.0 g 3 Hydrogen(50 psi) overnight 4 Tetrahydrofuran 22 mL 5 Ethyl Acetate 10 mL

In a 500 mL Parr shaker is placed the Z-valine protected benzyl ester(1-5) (2.50 g, 3.96 mmol) and the solid is dissolved in a mixture of THF(22 mL) and ethyl acetate (10 mL). To this is then added 10% Palladiumon Carbon (2.0 g) in a single lot and the resulting suspension ishydrogenated at 50 psi at room temperature for overnight. LC/MS at thistime of a small filtered aliquot, shows complete absence of startingmaterial and the presence of the desired material (M+1=409). Theremaining suspension is filtered through a Celite pad and the pad washedwith THF. Evaporation of solvent leaves a light yellow semi-solid whichupon trituration with isopropanol produces an off-white solid. The solidis collected by filtration through a Buchner funnel to provide 1.28 g(80% yield) of essentially pure pro-drug ester 1. LC/MS: (+) ESI:m/z=409.0 [M+1]; retention time=0.40 min. Melting Point: Decomposesbetween 140 to 145° C. Appearance: Off-white solid. Analytical HPLC;Column=Phenomenex Luna HILIC (reverse phase): Mobile Phase: A=0.05%H₃PO₄ in Water, B=0.05% H₃PO₄ in CH₃CN: Gradient: 5% A to 50% B over 20minutes, λ=205 nM; Retention Time: 3.8 minutes (Single Peak). ¹H NMR(400 MHz, d⁴-MeOD) δ 4.41-4.49 (m, 2H), 3.98-4.08 (m, 3H), 3.87-3.97 (m,2H), 3.57 (dd, J=9.6, 0.8 Hz, 1H), 2.28-2.39 (m, 1H), 2.22 (dd, J=12.8,4.8 Hz, 1H), 2.04 (s, 3H), 1.83 (dd, J=12.8, 11.6 Hz, 1H), 1.04-1.06 (m,6H); ¹³C NMR (400 mHz, D2O) δ 176.6, 174.6, 169.9, 96.4, 69.9, 68.4,67.8, 67.4, 67.2, 58.4, 52.3, 39.4, 29.4, 22.1, 17.3, 17.1. Final PurityEstimate: 96-97% (Based upon ¹H NMR integration in TrifluoroaceticAcid-D).

Example 4. Sialic Acid/Prodrug Single Dose PO Crossover PharmacokineticsStudy in Cynomolgus Monkeys

Test System Young adult (2.5-5 yo), Cynomolgus Macaques Drug StatusNon-naive # of Animals 3 animals (0♂, 3♀) Acclimation 14 days DosingRegimen PO on days 1 and 8

Day Test Article Dose Level Dose Route No of Animals 1 Sialic acid 100mg/kg PO 3 8 Prodrug 1 100 mg/kg PO

Test Substance Sialic Acid and Compound 1 Clinical Observations Oncedaily Body Weight Once weekly Blood Collection for PK PO arm: Pre-dose−1 and 0, 15, 30 minutes, 1, 2, 4, 8 and 24 hrs. Urine Collection for PKPre-dose overnight, 0-4 hrs, 4-8 hrs, 8-12 hrs, 12-24 hrs. Total volumeswere determined and 5 ml samples were preserved for possible futureanalysis. Blank plasma/urine Blank monkey plasma and urine (up to 100 mlif possible) Quality Assurance The study will be conducted according tothe principles of GLP.

A single oral dose crossover pharmacokinetic study of sialic acid (API)and prodrug (Compound 1—a valine ester of sialic acid as describedabove) was run in fasted cynomolgus monkeys (n=3). For this study, itwas essential that the GI tract of the in vivo model have somesimilarities to human metabolism in order for the Pep Ti transportersystem to be present, thus monkeys were chosen since they carry the sametransporter in the gut as humans.

The 100 mg/kg dose level chosen was based on what is known for dosing ofsialic acid which has passed complete toxicological evaluation and issafe up to 2,000 mg/kg NOAEL in dogs and rats. On Day 1, three femalecynomolgus monkeys were dosed with 100 mg/kg sialic acid (API) and onDay 8 the same three cynomolgus monkeys were dosed with 100 mg/kg of theprodrug. Serum was collected at the following timepoints: predose, then5 min, 15 min, 30 min, 1 hr, 2 hrs, 4 hrs, 8 hrs, 12 hrs and 24 hrspostdose. Urine samples were collected predose overnight, then atintervals 0-4 hrs, 4-8 hrs, 8-12 hrs and 12-24 hrs post dose. The datain FIG. 2A show the mean absorption values (n=3) of serum sialic acid onDays 1 and 8. The prodrug peak serum concentration is earlier (1 hr)than sialic acid API (2 hrs). While the T_(max) (1.623 μg/mL) for sialicacid API is higher than the prodrug (T_(max)=0.857 μg/mL), the extent ofthe absorption for both drugs are similar. The pharmacokinetic data inFIGS. 2B and 2C show group averages of sialic acid concentrations onDays 1 and 8.

Example 5: Single Dose Pharmacokinetic Studies of Sialic Acid Vs.Prodrugs in the Male Sprague Dawley Rat

The objective of this study was to investigate the pharmacokineticprofile of Sialic Acid and Prodrugs (Lactone 2C6, Lactone C6, Lactone C3and Lactone C9) following a single oral administration in the maleSprague Dawley rat. The structures of the Prodrugs are as follows:

Lactone 2C6:(1R,4R,5R,6R,7S)-6-acetomido-4[(R)-2-(hexanoyloxy)-1-hydroxyethyl]-7-hydroxy-2-oxo-3,9-dioxabicyclo[3.3.1]nonan-1-ylhexanoate:

Lactone C6:(1R,4R,5R,6R,7S)-6-acetomido-4[(R)-1,2-dihydroxyethyl]-7-hydroxy-2-oxo-3,9-dioxabicyclo[3.3.1]nonan-1-ylhexanoate:

Lactone C3:(1R,4R,5R,6R,7S)-6-acetomido-4[(R)-1,2-dihydroxyethyl]-7-hydroxy-2-oxo-3,9-dioxabicyclo[3.3.1]nonan-1-ylpropionate:

Lactone C9:(1R,4R,5R,6R,7S)-6-acetomido-4[(R)-1,2-dihydroxyethyl]-7-hydroxy-2-oxo-3,9-dioxabicyclo[3.3.1]nonan-1-ylnonanoate:

Fifteen (15) male Sprague-Dawley rats were assigned to 5 treatmentgroups (3 animals per group) that received either Sialic acid orProdrugs at a dose level of 175 mg/kg. Each dose was given as a singleoral gavage administration at a dose volume of 10 mL/kg. Blood samplesfor NANA and Prodrug analysis were collected at pre-dose (Day-2) and onthe day of dosing at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h and24 h post dose. Data provided in FIGS. 3A-3D.

A second experiment was conducted with a different set of Prodrugs(Lactone C9, Lactone C12, and Lactone C16). Lactone C12 and Lactone C16have the following structures:

Lactone C12:(1R,4R,5R,6R,7S)-6-acetomido-4[(R)-1,2-dihydroxyethyl]-7-hydroxy-2-oxo-3,9-dioxabicyclo[3.3.1]nonan-1-yldodeconoate:

Lactone C16:(1R,4R,5R,6R,7S)-6-acetomido-4[(R)-1,2-dihydroxyethyl]-7-hydroxy-2-oxo-3,9-dioxabicyclo[3.3.1]nonan-1-ylpalmitate:

Twelve (12) male Sprague-Dawley rats were assigned to 4 treatment groups(3 animals per group) that received either Sialic acid or Prodrugs at adose level of 200 mg/kg. Each dose was given as a single oral gavageadministration at a dose volume of 10 mL/kg. Blood samples for NANA andProdrug analysis were collected at pre-dose (Day-2) and on the day ofdosing at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h and 24 h postdose. Data provided in FIGS. 4A-4D. Without being bound by theory, it isproposed that the prolonged PK curves show how the fatty acid isdelaying clearance for the sialic lactone.

The patents and publications listed herein describe the general skill inthe art and are hereby incorporated by reference in their entireties forall purposes and to the same extent as if each was specifically andindividually indicated to be incorporated by reference. In the case ofany conflict between a cited reference and this specification, thespecification shall control. In describing embodiments of the presentapplication, specific terminology is employed for the sake of clarity.However, the invention is not intended to be limited to the specificterminology so selected. Nothing in this specification should beconsidered as limiting the scope of the present invention. All examplespresented are representative and non-limiting. The above-describedembodiments may be modified or varied, without departing from theinvention, as appreciated by those skilled in the art in light of theabove teachings.

1-77. (canceled)
 78. A compound selected from the group consisting of:


79. The compound of claim 78, wherein the compound is:


80. The compound of claim 78, wherein the compound is:


81. The compound of claim 78, wherein the compound is:


82. The compound of claim 78, wherein the compound is:


83. The compound of claim 78, wherein the compound is:


84. The compound of claim 78, wherein the compound is:


85. A pharmaceutical composition comprising a compound selected from thegroup consisting of:

or a pharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable carrier.
 86. The pharmaceutical compositionof claim 85, comprising the compound:


87. The pharmaceutical composition of claim 85, comprising the compound:


88. The pharmaceutical composition of claim 85, comprising the compound:


89. The pharmaceutical composition of claim 85, comprising the compound:


90. The pharmaceutical composition of claim 85, comprising the compound:


91. The pharmaceutical composition of claim 85, comprising the compound:


92. A sustained release pharmaceutical composition comprising a compoundof claim 78, or a pharmaceutically acceptable salt or solvate thereof,wherein: a) the release of the compound is over a period of about fourhours or more; and/or b) the pharmacological effect from the compoundlasts about four hours or more upon administration of the composition.93. A sustained release pharmaceutical composition comprising a compoundof claim 78, or a pharmaceutically acceptable salt or solvate thereof,wherein the composition, upon administration, provides a therapeuticallyeffective amount of the compound for about 4 hours or more.
 94. A methodfor treating a sialic acid deficiency in a patient in need thereofcomprising administering an effective amount of a compound of claim 78,or a pharmaceutically acceptable salt or solvate thereof.
 95. A methodfor treating a sialic acid deficiency in a patient in need thereofcomprising administering a compound of claim 78, or a pharmaceuticallyacceptable salt or solvate thereof; wherein upon administration, thecompound, or a pharmaceutically acceptable salt or solvate thereof,continuously provides a therapeutically effective amount of sialic acidfor about 4 hours to about 24 hours.
 96. The method of claim 94, whereinthe sialic acid deficiency is myopathy associated with sialic aciddeficiency.
 97. The method of claim 96, wherein the myopathy associatedwith sialic acid deficiency is Hereditary Inclusion Body Myopathy(HIBM), Nonaka myopathy, or Distal Myopathy with Rimmed Vacuoles (DMRV).